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Stem cells give scientists a new window into the biology of a rare disease

December 24, 2016

Today, Stanford pediatric cardiologist Marlene Rabinovitch, MD, and her team published new research that advances their quest to understand a serious — and very puzzling — lung disease. They’re studying pulmonary arterial hypertension, which frequently leads to heart failure. And their work, published in Cell Stem Cell, provides a great example of how stem-cell techniques can help researchers overcome an otherwise-insurmountable research challenge.

“These findings may allow us to develop precision-medicine treatments that are more individualized than we have now, and give us a new approach to screening possible drugs that is going to be a lot more promising,” Rabinovitch said.

PAH causes loss of the tiniest blood vessels in the lungs and makes larger lung blood vessels thicken and become dangerously narrow. The heart must pump harder and harder to get blood through the lungs, which sometimes weakens the heart so much so much that patients require a lung or heart-lung transplant.

About 15 percent of cases of PAH are inherited, and of those, many are due to a specific gene mutation with a strange pattern of inheritance: Although only one bad copy of the BMPR2 gene is enough to cause PAH, most people who carry it never develop the disease. Rabinovitch and her colleagues think that if they understood why carriers don’t get sick, they could use the biological quirks that protect carriers from their mutation to design better PAH drugs.

The ideal way to figure this out would be to compare endothelial cells — those lining the lung blood vessels — from patients and their unaffected carrier relatives. But endothelial cells from human lung blood vessels are very difficult to get. In the past, scientists could sometimes study a patient’s diseased lung if it was removed during a lung transplant, but almost never had access to healthy carriers’ lungs. Some research teams compared other kinds of cells from patients and carriers, but no one knew if the findings were relevant to the biology of PAH.

Rabinovitch’s team used stem cells instead. From 11 people whose families were affected by PAH — including both patients and healthy BMPR2 mutation carriers — the researchers took small skin samples and used them to make induced pluripotent stem cells, which were then converted into endothelial cells. (A prior paper they published a few months ago proved the concept behind this technique.)

Then they compared the patients’ and carriers’ endothelial cells. The findings help confirm that two drug targets Rabinovitch’s team has already identified are useful, since the target pathways are also active in the carriers’ cells. The team also found some new targets to try to correct, such as a cell-protecting factor that is reduced in patients but not in their unaffected family members.

The technique has other potential uses as well.

“This could be used to find what combinations of drugs might work based on restoring normal function rather than restoring a specific pathway in the cells,” Rabinovitch said. “That may be different in different individuals.” The team is now screening many drug combinations on the cells, and is excited about several other avenues of research that are opened by the ability to generate lots of patient-specific endothelial cells in the lab.

The technique will help make all sorts of hard-to-get cells much more accessible, Rabinovitch added, potentially advancing our understanding of the cellular mechanics behind many different diseases.

“Unless you can study the cell that’s abnormal, disease research is very difficult,” she said. “This gives us a supply of surrogate cells from different tissues. I think we’re going to learn a lot from these cells.”